Non-Invasive Determination of Cardiac
Output in Pre-Capillary Pulmonary
Hypertension
Frédéric Lador1*, Philippe Hervé2,3, Aurélien Bringard4, Sven Günther2,5, Gilles Garcia2,5,
Laurent Savale2,5, Guido Ferretti4,6, Paola M. Soccal1, Denis Chemla7, Marc Humbert2,5, Gérald Simonneau2,5, Olivier Sitbon2,5
1 Service de Pneumologie, Programme Hypertension Pulmonaire, Hôpitaux Universitaires de Genève, Genève, Switzerland, 2 AP-HP, Centre de Référence de l’Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Service de Pneumologie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France, 3 Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France,
4 Département des Neuroscience Fondamentales, Centre Médical Universitaire, Université de Genève, Genève, Switzerland, 5 Université Paris–Sud, Faculté de Médecine, Le Kremlin Bicêtre, France, 6 Dipartimento di Scienze Cliniche e Sperimentali, Università di Brescia, Brescia, Italy, 7 Département de Physiologie, Université Paris-Sud, Faculté de Médecine-EA4533-APHP, Le Kremlin Bicêtre, France *Frederic.lador@hcuge.ch
Abstract
Background
Cardiac output (CO) is a major diagnostic and prognostic factor in pre-capillary pulmonary hypertension (PH). Reference methods for CO determination, like thermodilution (TD), require invasive procedures and allow only steady-state measurements. The Modelflow (MF) method is an appealing technique for this purpose as it allows non-invasive and beat-by-beat determination of CO.
Methods
We aimed to compare CO values obtained simultaneously from non-invasive pulse wave analysis by MF (COMF) and by TD (COTD) to determine its precision and accuracy in
pre-capillary PH. The study was performed on 50 patients with pulmonary arterial hypertension (PAH) or chronic thrombo-embolic PH (CTEPH). CO was determined at rest in all patients (n = 50) and during nitric oxide vasoreactivity test, fluid challenge or exercise (n = 48).
Results
Baseline COMFand COTDwere 6.18± 1.95 and 5.46 ± 1.95 Lmin-1, respectively. Accuracy
and precision were 0.72 and 1.04 Lmin-1, respectively. Limits of agreement (LoA) ranged from -1.32 to 2.76 Lmin-1. Percentage error (PE) was±35.7%. Overall sensitivity and speci-ficity of COMFfor directional change were 95.2% and 82.4%, (n = 48) and 93.3% and 100%
for directional changes during exercise (n = 16), respectively. After application of a correc-tion factor (1.17± 0.25), neither proportional nor fixed bias was found for subsequent CO OPEN ACCESS
Citation: Lador F, Hervé P, Bringard A, Günther S, Garcia G, Savale L, et al. (2015) Non-Invasive Determination of Cardiac Output in Pre-Capillary Pulmonary Hypertension. PLoS ONE 10(7): e0134221. doi:10.1371/journal.pone.0134221 Editor: James West, Vanderbilt University Medical Center, UNITED STATES
Received: May 8, 2015 Accepted: July 7, 2015 Published: July 30, 2015
Copyright: © 2015 Lador et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This study was supported by an educational grant from the European Respiratory Society (RESPIRE postdoctoral fellowship program— Co-funded by the European Commission Seventh Framework Program (FP7)—Marie Curie Actions; MC-1630-2010) to Frédéric Lador.
Competing Interests: The authors have declared that no competing interests exist.
determination (n = 48). Accuracy was -0.03 Lmin−1 and precision 0.61 Lmin−1. LoA ranged from -1.23 to 1.17 Lmin−1and PE was±19.8%.
Conclusions
After correction against a reference method, MF is precise and accurate enough to deter-mine absolute values and beat-by-beat relative changes of CO in pre-capillary PH.
Introduction
Pre-capillary pulmonary hypertension (PH) is a haemodynamic condition that may lead to right heart failure, and that is defined by an increased resting pulmonary artery mean pressure (mPAP) due to elevated pulmonary vascular resistance (PVR) [1]. Consequently, cardiac out-put (CO), is a key diagnostic parameter and a major prognostic factor in diseases like pulmo-nary arterial hypertension (PAH) and chronic thromboembolic pulmopulmo-nary hypertension (CTEPH) [1,2], both characterized by such a condition.
Classical methods for CO measurement require right heart catheterisation (RHC) where the reference method is the direct Fick, although thermodilution (TD) or indirect Fick methods are widely preferred because of their relative simplicity in the clinical setting [1]. Hence, the availability of new, simple, reliable and non-invasive method for CO determination at rest and for CO changes in response to pharmacological interventions or during metabolic and volemic changes is desirable.
A promising technique for this purpose called Modelflow (MF) [3], relies on arterial pulse pressure wave analysis. Once corrected against a reference method, MF was shown to be a reli-able and accurate procedure in healthy humans [4], requiring only the application of a finger plethysmographic cuff to the patient for the continuous monitoring of pulse pressure profiles, thus being simpler than any other method proposed so far.
To the best of our knowledge, the accuracy and precision of MF was never assessed in pre-capillary PH. This study aims to evaluate MF in PAH and CTEPH patients, by comparing CO values obtained by MF (COMF) with values simultaneously determined on the same patients by
TD (COTD) during RHC procedures.
Materials and Methods
Study population
Seventy consecutive patients from the outpatient clinic and who underwent RHC for suspected or diagnosed pre-capillary PH within their routine workup were invited to participate (Fig 1). Patients with cardiac shunts were excluded, TD being potentially inaccurate in this condition. Patients with PH due to left heart disease (diagnostic Group 2 according to WHO classifica-tion, post-capillary PH) or PH with unclear or multifactorial mechanisms (diagnostic Group 5) were also excluded. In order to assess a homogeneous population, patients with PH due to lung disease were excluded because the physiopathology of pre-capillary PH is different in this group (diagnostic Group 3). 2 patients were also excluded from the study due to poor or no fin-gertip pulse pressure signal due to systemic sclerosis. Screening was not proposed to patients hospitalized in intensive care unit with acute right heart failure, haemodynamic shock or other life threatening condition. Analyses was finally performed on fifty patients with PAH (diagnos-tic Group 1, n = 30) or CTEPH (diagnos(diagnos-tic Group 4, n = 20). This study was approved by a
local ethics committee (comité de protection des personnes, Ile de France VIII, Hôpital Ambroise Paré, Boulogne-Billancourt, France) and was performed in the French reference centre for severe PH in Paris. All patients gave written informed consent.
Right heart catheterisation
Haemodynamic evaluation was performed in a supine position. Electrocardiogram and arterial oxygen saturation (pulse oximetry) were monitored continuously. Mean systemic arterial pres-sure (MAP) was meapres-sured at the brachial artery (Dynamap 1800; Critikon, Tampa, FL, USA). RHC was performed using the modified Seldinger technique with an 8F sheath inserted in the jugular, basilic or cephalic vein. The Swan-Ganz catheter was a 7F, two-lumen, TD and pres-sure-measuring tipped catheter (Corodyn TD; Braun Medical, Bethlehem, PA, USA). The zero-level reference was determined at mid-thoracic line. Resting haemodynamic evaluation included measures of right atrial pressure (RAP), mPAP, pulmonary artery wedge pressure (PAWP), COTD. PVR was calculated as (mPAP–PAWP)/ COTD, and systemic vascular
Fig 1. Study profile. PH: Pulmonary hypertension; LHD–PH: PH due to left heart disease; ILD–PH: PH due to interstitial lung disease; PAH: Pulmonary arterial hypertension; CTEPH: Chronic thromboembolic PH.
resistance as (MAP–RAP)/ COTD. Cardiac index was calculated as CO divided by body surface
area. Fluid challenge was performed by infusion of 500 ml of isotonic saline solution in five minutes, and haemodynamic parameters reassessed afterward. Vasoreactivity test was per-formed with inhaled nitric oxide according to current recommendations [1] prior to haemody-namic reassessment.
Cardiac output by thermodilution
In each patient, the positioning of the Swan-Ganz probe was confirmed by fluoroscopic con-trol. COTDwas determined by injection of 10 ml of iced-cold sterile, isotonic glucosaline
solu-tion through the proximal catheter’s lumen. The time course of temperature changes was recorded by the thermistor at the distal end of the probe. Three consecutive bolus injections were performed for each condition. The mean value of the three measurements was calculated if the difference between highest and lowest values was 10%. Otherwise, two more measure-ments were performed, the highest and lowest values were deleted, and the mean value of the three remaining measurements was calculated.
Cardiac output by Modelflow
COMFwas determined from continuous non-invasive recording of arterial pulse pressure
profiles by a Portapres system (TNO-TPD, Amsterdam, The Netherlands). The photoplethys-mographic cuff of Portapres was positioned on the index or middle finger contralateral to the vascular lines. The zero-level reference was placed according to the manufacturer’s instruc-tions. From pulse pressure profiles, beat-by-beat heart rate (HR) and stroke volume (SV) were calculated with the MF model, using the Beatscope 1.1a software (TNO-TPD, Amsterdam, The Netherlands) developed for this purpose.
The MF method for the beat-by-beat assessment of CO makes it possible to reconstruct aortic blood flow by simulating a three-element non-linear and time varying model of aortic compliance [3]. Numerical integration of flow during systole then yields SV. COMFis finally
computed as SV times the corresponding HR.
The COMFvalue in each condition was the mean value calculated over 100 consecutive
beats, starting simultaneously to the first of each series of COTDprocedure. Individual
correc-tion factors were calculated with the resting (basal) values as described elsewhere [4] and used to recalculate COMF(COMFcorr.) in other conditions.
Exercise haemodynamics
Exercise haemodynamic evaluation was performed supine on an electromagnetically-braked cycle ergometer (Cycline 100; Tecmachine, Andrezieux-Boutheon, France) secured to the cath-eterization table. Prior to exercise, 5 min of rest with feet installed on the bicycle (raised legs) were observed to ensure haemodynamic steady state after the expected increase of blood venous return to the heart (considered as“bicycle rest”). Then the patient pedalled at 60 rpm, the workload being increased stepwise by 20 W every 3 min from freeload cycling to a maxi-mum of 60 W, depending on patient’s functional tolerance. CO was determined during the last minute of each exercise level. All measures were obtained at steady HR and pulmonary artery pressure.
Statistics
Data are given as mean ± standard deviation (SD), unless otherwise stated. Data comparisons were performed by t-test for paired observations. Differences were considered significant when
p< 0.05. Coefficient of variation was calculated as mean divided by SD for baseline CO values. Linear relationships were analysed by linear regression, accounting for the error on both X-and Yaxis. The York algorithm [5] implemented under Matlab (version 7.13.0.564, Math-Works, Natick, MA, USA) was used, allowing calculation of confidence intervals for intercept (a ± 1.96SD) and slope (b ± 1.96SD), and estimation of proportional bias (a significantly
dif-ferent from 1) and fixed bias (b significantly different from 0) between the two methods. Bland–Altman analyses [6] were performed to determine the degree of agreement between COMFand COTDand between COMFcorr.and COTD. The mean bias (accuracy), precision, 95%
limits of agreements (LoA) and percentage error (PE) were calculated. Sensitivity and specific-ity of COMFfor directional COTDincrease or decrease in response to any procedure were
deter-mined. A directional change was considered false-negative when an increase of COTD 10%
was not accompanied by a COMFincrease 10%. A directional change was considered
false-positive when a COTD increase< 10% or any COTDdecrease was accompanied by an increase
of COMF 10%.
Results
The clinical and haemodynamic data at baseline are shown in Tables1,2and3. The conditions and number of simultaneous COTDand COMFmeasurements are shown inTable 4. Baseline
uncorrected COMFand COTDwere 6.18 ± 1.95 and 5.46 ± 1.95 Lmin-1, respectively, (p<0.05, Fig 2A). The coefficients of variation were 10.63% and 5.66% for COMFand COTD, respectively
(p<0.01). The Bland–Altman plot for baseline CO values appears inFig 2B. Accuracy and pre-cision were 0.72 and 1.04 Lmin-1, respectively. LoA ranged from -1.32 to 2.76 Lmin-1. PE was ±35.7%. The relationships between COMFand the corresponding COTDare reported inFig 3A, 3B and 3C. For CTEPH (n = 43), PAH (n = 55) and overall (n = 98), the intercepta was 0.207 ± 0.336, 0.516 ± 0.294 and 0.493 ± 0.209, respectively. Corresponding slopeb was 1.167 ± 0.062, 1.082 ± 0.043 and 1.095 ± 0.034 Lmin-1, respectively. A proportional bias was found for CTEPH (Fig 3A). Merging groups implied both proportional and fixed bias (Fig 3C).
Table 1. Baseline characteristics of the study population.
PAH (n = 30) CTEPH (n = 20)
Not operated (n = 14) Operated (n = 6)
Age yrs 48.7± 15.6 64.3± 11.0 56.2± 19.8 Female % 60.0 57.1 66.7 BMI kg.m-2 25.0± 5.1 25.4± 4.9 31.5± 5.8 BSA m2 1.77± 0.19 1.76± 0.23 1.89± 0.18 MAP mmHg 90.9± 14.2 104.3± 20.4 95.0± 19.5 RAP mmHg 5.8± 3.1 7.4± 5.2 4.3± 3.9 mPAP mmHg 48.6± 14.9 43.0± 13.0 26.3± 7.6 PAWP mmHg 9.2± 3.7 6.2± 2.4 9.3± 3.3 CO Lmin-1 6.0± 2.1 4.3± 1.3 5.5± 0.7 CI Lmin-1m-2 3.4± 1.0 2.4± 0.5 2.9± 0.2 PVR WU 7.5± 4.4 9.5± 4.5 3.2± 1.3 SVR WU 15.9± 6.1 24.7± 10.1 17.1± 5.8
Data are presented as mean± SD unless otherwise stated. BMI: Body mass index; BSA: Body surface area; MAP: Mean systemic arterial blood pressure; RAP: Right atrial pressure; mPAP: Pulmonary artery mean pressure; PAWP: pulmonary artery wedge pressure; CO: cardiac output, determined by thermodilution; CI: Cardiac Index; PVR: Pulmonary vascular resistance; SVR: Systemic vascular resistance; WU: Wood units.
The Bland–Altman plot for merged groups is shown inFig 3D. The accuracy was 1.05 Lmin−1
(p<0.01). The precision was 1.20 Lmin-1. LoA ranged from -1.30 to 3.40 Lmin-1. PE was ±37.9%. The overall sensitivity and specificity of COMFfor directional change in response
to any of the experimental manoeuvres (nitric oxide vasoreactivity test, fluid challenge or exer-cise) were 95.2% and 82.4%, respectively (n = 48). Mean calibration factor for COMF
was 1.17 ± 0.25. COMFcorr.in all conditions except baseline (which was used to determine
the correction factor) are plotted against the corresponding COTDinFig 4A. The regression
line was characterized bya and b of 0.094 ± 0.254 Lmin−1and 0.990 ± 0.038, respectively. Nei-ther proportional nor fixed bias was found. The Bland–Altman plot (Fig 4B) showed an
Table 2. Diagnosis and treatment of the PAH population (%).
Subjects 30
WHO diagnostic subgroup
Idiopathic 17 (56.7)
Heritable 2 (6.7)
Drugs and toxin induced 1 (3.3)
Associated# 9 (30.0)
Pulmonary veno-occlusive disease 1 (3.3)
Treatment naive (newly diagnosed§) 7 (23.3)
No specific drug therapy 1 (3.3)
PAH-specific drug therapy 22 (73.3)
ERA 16 (72.7)
PDE5i 12 (54.5)
Prostanoid 7 (31.8)
CCB 1 (4.5)
Monotherapy 11 (50.0)
Double combination therapy 7 (31.8)
Triple combination therapy 4 (18.2)
doi:10.1371/journal.pone.0134221.t002
Table 3. Diagnosis and treatment of the CTEPH population (%).
Subjects 20
Newly diagnosed§ 12 (60.0)
Inoperable** 2 (10.0)
Operated¶ 6 (30.0)
PAH-specific drug therapy 5 (25.0)
ERA 5 (100)
PDE5i 4 (80.0)
Monotherapy 1 (20.0)
Double combination therapy 4 (80.0)
ERA: Endothelin receptors antagonists; PDE5i: phosphodiesterase-5 inhibitors; CCB: Calcium channel blockers. #Patients with PAH associated to connective tissue disease (n = 1), HIV infection (n = 2), Portal hypertension (n = 2) and Congenital heart disease after corrective cardiac surgery (n = 4).
§Patients diagnosed at the time of the present study. **Due to distal lesions.
¶ Patients with persisting hemodynamic impairment at least 3 months after pulmonary endarterectomy (PEA).
accuracy of -0.03 lmin−1(NS). Precision was 0.61 Lmin−1. LoA ranged from -1.23 to 1.17
Lmin-1. PE was ±19.8%. CO
MFcorr.values at exercise (n = 16) are plotted against their
corre-sponding COTDinFig 5A. The regression equation had intercepta and slope b of
-1.093 ± 0.760 and 1.117 ± 0.091 Lmin−1, respectively. Neither proportional nor fixed bias was
found. The Bland–Altman plot (Fig 5B) revealed a -0.15 Lmin−1accuracy (NS). Precision was 0.65 Lmin−1. LoA ranged from -1.42 to 1.12 Lmin-1. PE was ±16.4%. The changes of CO
MFcorr
(ΔCOMFcorr) from baseline for each subject are plotted against the correspondingΔCOTDin Fig 5C. The sensitivity and specificity of COMFfor directional change in response to exercise
were 93.3%. and 100%, respectively (n = 16). In one case, a COMFdecrease< 10% (-0.22
Lmin-1) did not accompany a CO
TDincrease 10% (+0.70 Lmin-1) and was considered a
false negative.
Table 4. Conditions and number of simultaneous COTDand COMFmeasurements.
n Rest (baseline) NO testing Fluid Challenge Bicycle rest Bicycle exercise Total
PAH 30 7 4 5 9 55
CTEPH 20 9 1 6 7 43
Total 50 16 5 11 16# 98
Repartition of the different single simultaneous COTDand COMFmeasurements. A total of 98 CO measurements were performed in the 50 patients. Each
COTDis the mean of 3 TD measurements (seeMethods). Each COMFis the mean of 100 consecutive beat-by-beat values (seeMethods). 26 patients
(PAH n = 12, CTEPH n = 14) had a total of 48 measurements in conditions other than basal (PAH n = 25, CTEPH n = 23). #6 patients performed incremental exercise (PAH n = 4, CTEPH n = 2) with the workload being increased stepwise by 20 W every 3 min to a maximal workload of 60 W depending of patient functional tolerance for a total of 16 CO determined during steady exercise (PAH n = 9, CTEPH n = 7). NO: Nitric oxide
vasoreactivity test; Fluid Challenge: CO determined after infusion of 500 ml of isotonic saline solution infive minutes; Bicycle rest: CO determined after 5 min of rest with feet positioned on the pedals with raised legs.
doi:10.1371/journal.pone.0134221.t004
Fig 2. Comparison of baseline values of COMFand COTD. Simultaneous determination of cardiac output by thermodilution (COTD) and Modelflow (COMF)
in 50 patients with pre-capillary pulmonary hypertension. (A) The figure describes median (line), 25th to 75th percentile (box), 5th to 95th percentile (whiskers) and the dots represent outliers. The mean values for COTDand COMFwere 5.46± 1.95 Lmin-1and 6.18± 1.95 Lmin-1, respectively (p<0.05). (B)
Difference between resting COMFand COTDvalues plotted against their mean. Broken line represents the mean (+ 0.72 Lmin-1) and the solid lines the 95%
limits of agreement (-1.32 to + 2.76 Lmin-1). doi:10.1371/journal.pone.0134221.g002
Fig 3. Relationship between COMFand COTD. COMF determined in 50 patients (98 values) under various conditions (rest, fluid challenge, NO testing and
exercise). COMFvalues were plotted against the corresponding COTDvalues for CTEPH patients (A) PAH patients (B) and all 50 patients (C). (D) Difference
between COMFand COTDvalues plotted against their mean. In (A), (B) and (C), the broken lines correspond to the lines of equality, solid lines are the mean
regression lines and dotted lines delimit the confidence interval of the regression lines. In (D), broken line represents the mean (+ 1.05 Lmin-1) and the solid
lines the 95% limits of agreement (-1.30 to + 3.40 l.min-1). doi:10.1371/journal.pone.0134221.g003
Discussion
The results of the present study show that MF applied to non-invasive pulse pressure profiles, once corrected against a reference method, offers a precise and accurate determination of CO in patients with PAH and CTEPH.
Uncorrected COMFoverestimation of COTDwas confirmed by the ranges of regression lines
inFig 3, displaced above the equality line when plotting COMFagainst COTDin CTEPH and
merging groups. When applied to the PAH group only (Fig 3B), however, linear regression showed neither fixed nor proportional bias. These results are consistent with previous data, comparing MF applied to peripheral pulse pressure profiles to different reference methods in various clinical settings and populations [4,7,8] and confirm the need of a correction when determination of absolute CO values, more than relative changes, is needed. Conversely, when compared to TD at rest, non calibrated MF applied to pulse waves obtained from intra-arterial signal in cardiac surgery patients was reliable and superior to other CO monitoring devices, with acceptable LoA and PE [9]. These results were confirmed by a recent meta-analysis [10]. Another study compared COMFfrom arterial pulse pressure profiles recorded with Portapres
and from intra-arterial radial catheter in healthy subjects [11]: non-invasive CO was signifi-cantly and systematically higher than CO from intra-arterial signal. The systematic difference was attributed to differences in pulse wave between radial and finger arteries. This may also partially explain the overestimation of COMFas compared to COTDin our study. Here, PE
of COMFslightly exceeded the ±30% limit admitted for allowing interchangeability of a new
technology with TD, as suggested by a meta-analysis of CO validation studies published by
Fig 4. Relationship between COMFcorr.and COTD. COMFcorr. determined in 26 patients (48 values). (A) For each subject, COMFcorr.values were plotted
against the corresponding COTDvalues. The broken line corresponds to the line of equality, solid line is the mean regression lines and dotted lines delimit the
confidence interval of the regression lines. (B) Difference between COMFcorr.and COTDvalues plotted against their mean. Broken line represents the mean
(-0.03 Lmin-1) and the solid lines the 95% limits of agreement (-1.23 Lmin-1to +1.17 Lmin-1).
Critchley and Critchley [12]. Still, the LoA and PE values of our study were smaller than those obtained in PH patients for TD against direct Fick [13], thoracic bioimpedance against TD
Fig 5. Relationship between COMFcorr.and COTDduring exercise. COMFcorrdetermined in 6 patients during exercise procedure. (A) For each subject,
COMFcorrvalues were plotted against the corresponding COTDvalues. The broken line corresponds to the line of equality, solid line is the mean regression
lines and dotted lines delimit the confidence interval of the regression lines. (B) Difference between COMFcorrand COTDvalues plotted against their mean.
Broken line represents the mean (-0.15 Lmin-1) and the solid lines the 95% limits of agreement (-1.42 l.min-1to +1.12 Lmin-1). (C) For each subject and workload, the increase (Δ) in COMFcorrfrom rest was plotted against the same corresponding COTDincrease (ΔCOTD). The six different targets correspond to
the six different patients. The broken line corresponds to the line of equality. doi:10.1371/journal.pone.0134221.g005
[14] and transthoracic bioreactance against TD or indirect Fick [15]. It is noteworthy that these two latter alternative methods for non-invasive CO determination are also promising, as discussed in a recent review that focused its performances in the assessment of fluid respon-siveness using passive leg raising test and cardiac output response to exercise stress testing [16]. In our study, COMFwas not compared with direct or indirect Fick: any assumption of a better
correlation between MF and these methods would be speculative. Previously, determination of CO changes by acetylene rebreathing showed good correlation with COTDchanges in PAH
patients [13]. That technique was considered acceptable in most cases, despite LoA and PE similar to the present ones. Other promising techniques, such as cardiac magnetic resonance [17,18] or echocardiography [19,20], raise real interest in CO determination but require the advanced expertise of a dedicated technician and a specific setting.
We didn’t aim at showing whether uncorrected MF could be interchangeable with TD. Pre-vious studies that addressed this question showed that this is not so [21]. Moreover, contrary to other clinical conditions, RHC is mandatory for PAH or CTEPH diagnosis [1]. Thus, since these patients undergo anyway RHC, it would be easy to obtain a correction factor [4,22] and calibrate MF with basal TD in order to use the former for subsequent CO determination during various conditions.
In this study, we also showed that MF detects significant directional changes of CO
associated to vasoreactivity testing, fluid challenge or exercise (Figs4and5). Also transthoracic bioreactance was claimed to reliably detect dynamic, directional CO changes following vasor-eactivity testing with a sensitivity and specificity of 88.9% and 100%. Our results are similar to those reported in this publication [14]. In a consistent manner with previous reports [23], we assumed that a COTDvariation would be significant when10%, although an actual significant
variation should overtake the magnitude of the least significant change. Thus, the minimum change that a device must measure to detect a real change is given by the formula: precision multiplied byp2 [24]. From our data, the least significant change corresponded to a 9.2% change. When applying this limit for calculation of sensitivity and specificity, no value was reclassified.
The third finding of our study is that, once corrected against a reference method, MF showed acceptable accuracy and precision in determining CO changes (Figs4and5). In fact, COMFcorrrevealed LoA and PE below the limits for inter-changeability with TD. This suggests
that COMFcorrmay constitute an alternative method to TD for serial CO measurements on the
same patient during the same procedure. The range of individual correction factors corre-sponds to that of healthy subjects [4]. So, MF application may simplify and shorten any RHC protocol where several CO measurements are required [1,25]. Moreover, it makes possible to explore CO changes with a beat-by-beat resolution, allowing opportunities to describe more precisely cardiovascular adjustments during transients, like exercise onset in PH patients. In fact, there is a growing interest in exploring exercise haemodynamics in pulmonary vascular diseases. For instance, the establishment of multipoint pressure-flow (mPAP–CO) relation-ships during exercise was recently shown to better describe pulmonary vascular resistive prop-erties than PVR calculated only from resting values [26,27]. Our group also recently showed that exercise haemodynamics may also give invaluable information for unmasking pulmonary vascular disease [28], assessing PAH severity and driving its therapeutic approach [29]. Like-wise, haemodynamic response to exercise may be useful in patients with high risk of developing PAH such as relatives of patients with heritable PAH [30] or patients with diseases associated with high risk of developing PAH or resting mPAP values between 20 and 25 mmHg [31]. Car-diodynamic exploration with determination of PVR changes at exercise may also help unmask-ing PH due to left heart disease that could mimic PAH at rest and induce misdiagnosunmask-ing [32]. Finally, the most recent guidelines for PAH treatment strongly recommend the inclusion of
patients in supervised exercise rehabilitation programmes [2], where the possibility of easy-access non-invasive monitoring of CO changes is desirable.
This study has several limitations. TD is not the gold standard for CO determination: the comparison with the direct Fick method may provide different results. Yet, TD reflects every-day clinical reality and common practice in PH reference centres and we aimed at comparing MF to routine procedure. MF is unusable in patients with poor finger pulse-wave signal, as it was the case in the present study for two patients with PAH associated to connective tissue dis-eases (CTD). This may be an issue in centers were PAH associated to CTD is the most repre-sented population. It is also unsure if MF and TD correlation would be different in patients with cardiac arrhythmias, which was not the case for the patients included in our study. Finally, it is still uncertain that the validity of the individual correction factor determined during RHC persists over time or in different clinical testing. To date, individual correction of MF needs to be determined against a reference method at every new exploration. That said, our data still confirm that MF is reliable for relative CO changes even if no correction factor is applied. It is also noteworthy that the model of aortic compliance used to compute COMFwas developed
from data obtained on healthy subjects [3]. So it may be that the characteristics of aortic com-pliance in PAH or CTEPH patients are different, inducing here a potential bias. In our study, this issue was counterbalanced by the individual correction factors. Yet it may well impair the utilization of a population correction factor, which moreover would have been unwise to use in our study, considering the size of the study population and the variables to be included in the analysis. We acknowledge that this may be seen as a limitation of our study. Nevertheless, the mean correction factor determined in the present work was similar to those obtained previ-ously in healthy subjects against another reference method [4].
Conclusions
MF is a simple and reliable method for detecting CO changes in pre-capillary PH. Once cor-rected against a reference method, it is precise and accurate enough to evaluate absolute CO changes in response to exercise, fluid challenge or vasoreactivity testing. MF may simplify hae-modynamic evaluation of pre-capillary PH in clinical practice and widen the range of follow-up and exploratory opportunities as it could potentially be used to study CO changes outside the RHC laboratory on a beat-by-beat basis.
Supporting Information
S1 Table. General Data. The table gives all the individual studied baseline parameters of the study population (n = 50) reported in theFig 2, Tables1–3.
(PDF)
S2 Table. Data COMF−COTD. This table gives all the individual conditions and number of
simultaneous COTDand COMFmeasurements reported in theFig 3andTable 4(n = 98).
(PDF)
S3 Table. York analysis. This table gives the calculated confidence intervals of linear regression obtained with York algorithm for intercept (a ± 1.96SD) and slope (b ± 1.96SD), and confi-dence interval of COMF(Fig 3) or COMFcorr. (Figs4and5) against any COTD.
(PDF)
S4 Table. Data COMFcorr.−COTD. This table gives all the conditions and number of
simulta-neous COTDand COMFcorr. measurements reported in theFig 4(n = 48).
Acknowledgments
The authors would like to thank Dr. Tiziano Binzoni for fruitful discussion about the data.
Author Contributions
Conceived and designed the experiments: FL PH MH GS OS. Performed the experiments: FL PH AB SG GG LS. Analyzed the data: FL PH AB GF PMS DC MH GS OS. Contributed reagents/materials/analysis tools: FL AB GF PMS DC MH GS OS. Wrote the paper: FL PH AB GF PMS DC OS.
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